Pharmaceutical compositions, particularly ophthalmic, otic and nasal compositions, that are utilized multiple times by a patient are often referred to as being of a “multi-dose” nature. Such compositions can be manufactured under sterile conditions via procedures that are well known to those skilled in the art. However, once the packaging for a product is opened, such that the composition contained therein is exposed to the atmosphere and other sources of potential microbial contamination (e.g., the hands of a human patient), the sterility of the product may be compromised. Thus, such pharmaceutical compositions typically require the use of a preservative to aid in the prevention of growth of fungal and bacterial microbes. Moreover, such preservatives are typically required to assure that those compositions comply with preservation efficacy requirements of the United States Pharmacopeia (“USP”) and/or analogous guidelines in other countries.
While such preservatives are typically needed to provide required preservation efficacy, those same preservatives can exhibit variable degrees of discomfort and/or toxicity to bodily tissue. Moreover, multi-dose pharmaceutical compositions are often designed to repeatedly come in to contact with particular portions of the body (e.g., the cornea of the eye or other bodily tissue), either directly or indirectly, and those body portions can be particularly sensitive to exogenous chemical agents. Consequently, in order to minimize the potential for harmful effects to such tissue, it is preferable to use anti-microbial preservatives that are relatively non-toxic to that tissue, and to use such preservatives at relatively low concentrations.
A desired balance between anti-microbial efficacy and potential toxicological effects of anti-microbial preservatives is often difficult to achieve. More specifically, the concentration of an antimicrobial agent necessary for the preservation of multi-dose pharmaceutical formulations from microbial contamination may create the potential for toxicological effects on the cornea and/or other bodily tissues. Using lower concentrations of the anti-microbial agents generally helps to reduce the potential for such toxicological effects, but the lower concentrations may be insufficient to achieve the required level of biocidal efficacy (i.e., antimicrobial preservation).
In view of this balance, the pharmaceutical industry continues to seek antimicrobial agents that provide a high degree of preservation efficacy while exhibiting a relatively low degree of toxicity.